Synthesis, antimicrobial and QSAR studies of some new thiadiazepine derivatives

Abstract
A new series of thiadiazepine derivatives 3a-l were synthesized from base catalysed reaction
between chalcones and triazoles. They were characterized by advanced spectral techniques
like IR, 1HNMR and mass spectroscopy and their antimicrobial studies were carried out. 3i
exhibited excellent activity against gram +ve bacteria. 3g displayed significant antifungal
activity. The logarithm of zone of inhibition of microorganisms were used for studying the
quantitative structure activity relationships (QSAR) of the newly synthesized thiadiazepines
and were carried out using Easy QSAR 1.0 by simple linear regression analysis. PaDEL
Descriptor 2.13 predicted Eccentric connectivity index (ECCEN) and Chi path to be the best
correlated QSAR model for antibacterial and anti-fungal activity of thiadiazepines against
Staphylococcus aureus and Asper gillusniger respectively. The development of the best
QSAR model for antimicrobial activity for thiadiazepines was confirmed by the high
correlation between the observed and the predicted Log ZOI values.
1. Introduction
Currently, there is a wide range and spectrum of effective antimicrobials. However the
emerging problem of multidrug resistance is proving to be a bigger challenge than the
infections themselves in the pre-antibiotic era. Antimicrobial resistance is a growing threat
worldwide. Resistance mechanisms have been found for every class of antimicrobial agents
and the search for new antimicrobials effective against various multiresistant strains is
probably one of the most difficult challenges of medicinal chemistry. Development of new
classes of antimicrobials is essential for the future. 1,2,4-Triazole, a five member heterocyclic
with three nitrogen atoms in the ring which are by far the best-known class of triazoles,
comprises wide variety of medicinal activities like antifungal, antimicrobial, antiinflammatory, hypoglycemic, antidepressant, antitubercular, analgesic, anticancer and
anticonvulsant1-8. Some of the marketed formulations which contain triazole ring are
Terconozole, Itraconazole, Fluconazole, Bittertanol (fungicides), Trazodone (antidepressant)
and Triazolam (sedative and hypnotic). 1,2,4-Triazole is an important emerging moiety in
pharmaceutical study and a lot of work can be carried out on this molecule for obtaining
better therapeutic activity.The synthesis of compounds belonging to thiadiazepine series
constitute an important research area due to their interesting diverse biological activities such
as antibacterial, antifungal, antiHIV, analgesic, anticoagulant, and antidepressant properties916. Structural requirements for a molecule to show any biological activity is defined by
structure activity relationship studies. QSAR studies are relevant as the biological activity of
a molecule is dependent on its physicochemical properties. Prompted by these observations
and in continuation of our research work on nitrogen and sulphur containing biologically
active molecules, we report the synthesis and QSAR analysis of some new triazolothiadiazepines.

2. Materials and methods

2.1 Chemistry
3-Substituted-4-amino-5-mercapto-1,2,4-triazoles 1a-b were synthesized through
multistep sequential reaction from different substituted phenols17. The condensation of
substituted aromatic aldehydes with 4-substitutedacetophenone yielded six chalcones18 2a-f.
The reaction between triazoles 1a-b and chalcones 2a-f gave the twelve new thiadiazepines19
3a-l (Scheme-1). The chemicals used for this study were obtained from Merck and Aldrich
Chemicals. Thin layer chromatography was conducted using 1:1 mixture of ethyl acetate and
hexane solution for chalcones and 1:4 mixture of ethyl acetate and benzene for thiadiazepines
as eluents to check their purity. The IR spectra were recorded in a Schimadzu FTIR 8400S
spectrophotometer using KBr pellets. 1H-NMR spectra were recorded in deuterated dimethyl
sulphoxide in an AV500 NMR spectrometer with tetramethylsilane as internal standard. The
mass spectra were recorded in a Schimadzu GCMS-QP5050 mass spectrometer. The
elemental analysis of all compounds done in Flash thermo 1112 series CHN analyser gave the
values within the permissible limit of 0.4 %. Melting points were determined by open
capillary method and are uncorrected. The IR, 1HNMR and MS were consistent with the
assigned structures. IR spectra of condensed thiadiazepines displayed disappearance of band
at 1665 cm-1 due to C=O str. of chalcone and at 2750 cm-1 due to SH str. of 5-substituted4-amino-3-mercapto-1,2,4-triazoles. 1H-NMR spectra of thiadiazepines showed the >CH-S
proton at 5 ppm and CH= proton at 7.5 ppm. The proton attached to nitrogen of
thiadiazepine ring was observed at 8.5 ppm. The solvent peak due to DMSO-d6 was observed
at 2.4 ppm.
2.2 Pharmacology Disc Diffusion Method (Kirby-Bauer Method)20 was employed to assess
the antimicrobial potential of thiadiazepines. The efficacy of thiadiazepines as antimicrobial
agents was studied against gram-positive bacteria S. aureus, gram-negative bacteria E. coli
and fungi A. niger. Thiadiazepines were dissolved in DMSO to make a concentration of 10
g/mL. DMSO, used as control showed no antibacterial activity. The petri plates were
initially plated with nutrient agar media, dipped in prepared thiadiazepine solution, placed in
swab cultured inoculated plates using sterile forceps, gently pressed and were incubated at 37
C for 24 h for antimicrobial and for a week for antifungal studies. Tetracycline and
Ketaconazole were used as standard antibacterial and antifungal drugs respectively. The
average diameters of inhibition zones of microbial growth around the discs were recorded.
2.3 QSAR studies The molecules were converted from 2D to 3D structures to perform the
QSAR studies. The descriptors for thiadiazepines were predicted using PaDEL software21.
Easy QSAR 1.0 was employed for simple linear regression analysis to study the correlation
between the Log ZOI values of thiadiazepines and the physicochemical descriptors. Various
statistical parameters like the square of the correlation coefficient (r2), the Fischers value of
significance (F) and the standard error of estimate (s)was used to choose the most agreeing
QSAR model22 and the correlation between the experimental and predicted antimicrobial
activity was studied using Easy QSAR tool.

3. Results and discussion The results revealed that most of the compounds showed moderate
antibacterial activity.3i with chloro and dimethoxy substituent exhibited relatively high
inhibitory effect on S. aureus.Thiadiazepines3c and 3d displayed high sensitivity against
E.coli. Compound 3g which had fluoro and dimethoxy substituents in the phenyl ring
demonstrated the best antifungal activity by inhibiting spore germination of A. niger. The
structure-antimicrobial activity relationship of the synthesized compounds revealed that the
compounds with halogen substituents exhibited maximum antimicrobial activity. This can be
attributed to the increased dipole moment in C-X bond which might have enhanced the
intermolecular interactions and hydrogen bonding leading to high antimicrobial potency of
the molecule. The observed and the predicted Log ZOI of thiadiazepines are listed in Table
1and the correlation between them is depicted in Fig.1 and Fig.2 respectively.
Table 1: Results of antimicrobial studies of thiadiazepines
Compound No.
S. aureus
A. niger
ZOI
(mm)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l

Observed Predicted ZOI

Log ZOI
Log ZOI
(mm)
11
2.398
2.87
0
07
1.946
2.21
07
19
2.944
2.94
12
0
0
0
10
2.303
2.43
08
06
1.792
1.77
05
14
2.639
2.60
23
0
0
10
25
3.219
2.60
13
07
1.946
1.90
07
10
2.303
2.15
08
04
1.386
1.47
05

Observed
Log ZOI
0
1.946
2.485
0
2.079
1.609
3.135
2.303
2.565
1.946
2.079
1.609

Predicted
Log ZOI
2.24
2.65
1.98
1.57
2.65
2.24
2.65
2.24
1.98
1.57

In the QSAR model developed by the simple linear regression analysis, the highest value of
the square of the correlation coefficient (r2 = 0.73), and the suitable values of F and s
(21.77and 0.73, respectively), were obtained when Log ZOI (antibacterial activity) of
thiadiazepines against S. aureus at 100 g/mL, was correlated with the ECCEN to identify the
descriptor contribution as presented in equation 1. ECCEN is a distance based molecular
structure descriptor and has been shown to give a high degree of predictability of
pharmaceutical compounds. It provides leads to the development of safe and potent bioactive
compounds. The lower the value of ECCEN, the higher would be the activity of
thiadiazepines against S. aureus as indicated by its negative sign.
4. Conclusion
Twelve new thiadiazepines synthesized by the reaction between chalcones and
triazoles were subjected to antimicrobial studies. Compound 3i and 3g was identified as the
most potent within this study with a promising antibacterial and antifungal potential against
S.aureus and A. niger. The parameters, ECCEN and SP-2, were remarkably related to the
antibacterial and anti-fungal activities of thiadiazepines against S. aureus and A. niger at 100

g/mL. The development of the best QSAR model was suggested by the correlation between
the observed and the predicted Log ZOI values for thiadiazepines. The potential of
thiadiazepines3i and 3g should be further explored for development of antimicrobial agents.
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